1. Jared Weiss, MD University of North Carolina 11/14/2014
The use of systemic anti-cancer therapy for elderly patients with metastatic NSCLC
Jared Weiss, MD
University of North Carolina
11/14/2014

2. What is the median age of presentation of NSCLC?40 50 60 70 80 90

3. Incidence of NSCLC in the US by age at diagnosis
Median age at diagnosis: 71
No. of patients
Figure 1. Incidence of NSCLC in the US by age at diagnosis. The median age at NSCLC diagnosis is approximately 71 years; however, over one-third of all patients are 75 years of age at diagnosis. (Data from SEER Cancer Statistics Review, At: Accessed October 22, 2004.)
Age at diagnosis (y)
Data from SEER Cancer Statistics Review,
SEER Cancer Statistics Review, At: Accessed October 22, 2004.

4. Metastatic Lung Cancer IS a disease of the elderly
¾ of lung cancer is metastatic (stage IV, incurable) at presentation
The median age of presentation with metastatic lung CA is 71
Therefor, to talk about geriatric lung cancer IS to talk about metastatic lung cancer and…
To talk about metastatic lung cancer IS to talk about a geriatric population.

5. The elderly are untreated…badly
Misperceptions about expected longevity of the elderly
Misperceptions about tolerability of treatments in the elderly
Misperceptions about efficacy of treatments in the elderly

6. What is the life expectancy of a 70 year old man
What is the life expectancy of a 70 year old man? How about a 70 year old woman?
Man 2 years, Woman 3 years
Man 5 years, Woman 7 years
Man 10 years, Woman 12 years
Man 12 years, Woman 14 years
Man 14 years, Woman 16 years

7. The elderly: In the absence of severe comorbidity, life expectancy is likely driven by the lung cancer
Age
Male Life expectancy
Female life expectancy 76 81 20 57 62 40 38 42 60 21 24 65 18 70 14 16 75 11 13 80 8 10 85 6 7 90 4 5 95 3
100 2
SSA acturial life table, cited in Weiss, 2013

8. “Traditional” view of Quality of Life
Chemo causes:
Nausea
Alopecia
Fatigue
Infections
Therefor, maximize quality of life by avoiding chemo.

9. An Alternative View of Quality of Life
Cancer growth causes:
*Pain
*Cough
*Shortness of breath
*Fatigue
*Organ Failure
*Thrombosis
*Hoarse voice
*Nausea
*Anorexia
Chemo can alleviate cancer suffering.
Better drugs and better supportive care means more tolerable anti-cancer therapy.
Symptoms of
progressive
cancer
Side-effects
of therapy

10. Ways out from Between the Rock (Side effects of treatments) and the Hard Place (Suffering Caused by cancer)
Geriatric Assessment
Direct data on efficacy and safety of treatments in the elderly
Drugs with improved efficacy and decreased toxicity
Need a rock and hard place picture

11. ELVIS: Chemo works in the elderly
Vinorelbine 30 mg/m2 days 1 & 8 every 21 days vs supportive care
1-year Survival 14% vs 32%
Favorable QoL Overall
ELVIS Group. J Natl Cancer Inst. 1999;91:66-72.

12. Issues in 1st line chemotherapy
Two drugs vs. one
Bevacizumab (Avastin)
Molecular options
Elderly-specific chemo?
Poor PS patients

13. Timeline for Chemo (Every regimen is different; just basic idea here)
Observe with imaging
until progression
Regimen 2:
Partner drug
+/-
Biologic
Treat to 4-6
cycles
PR or SD
Maintenance chemotherapy:
1. Stop carboplatin
2. Continue partner +/- biologic or
Just partner
Just biologic
New drug (pemetrexed or
erlotinib)
Regimen 1:
Carboplatin +
Partner drug
+/-
Biologic X
2-3 cycles
(cycle is three
weeks in most
regimens so
6-9 weeks
Imaging PD
Change chemo:
Carboplatin +
Different partner
+/-
Biologic
PR: Partial response
SD: Stable disease
PD: Progressive disease

14. CALGB 9730: Results by Age R A N D O M I Z E Carboplatin AUC = 6
Paclitaxel 225 mg/m2
Day 1 every 21 days
Stage IIIB/IV
NSCLC
N = 561
Paclitaxel 225 mg/m2
Day 1 every 21 days
Age < 70Age < 70
Chemo
Resp
Rate
Median
Survival
1-year
Paclitaxel
15%
6.8 mo
33%
Carbo/
Paxlitaxel
28%
9.0 mo
38%
Age ≥ 70
Chemo
Resp
Rate
Median
Survival
1-year
Paclitaxel
21%
5.8 mo
31%
Carbo/
Paxlitaxel
36%
8.0 mo
35%
Lilenbaum RC, et al. J Clin Oncol. 2004;23:

15. IFCT-0501 Trial of Platinum-Doublet Chemo for Advanced NSCLC in Patients 70-89Z E
Carboplatin day 1
paclitaxel days 1, 8, 15
Every 28 days
Erlotinib daily
Advanced NSCLC
Stage III or IV
Age 70-89
PS 0-2
N = 451
Vinorelbine or
Gemcitabine
days 1 & 8
Every 21 days
Erlotinib daily
Primary Endpoint: Overall survival
Terminated early by Data Safety Monitoring Board
Quoix EA, et al. ASCO Abstract 2.

16. Overall Survival and Progression-free survival in IFCT-0501 TrialOS
PFS
HR 0.64 (95% CI , p<0.0001)
HR 0.51 (95% CI , p<0.0001)
Quoix E, et al. Lancet. 2011;378:

17. Trial Design Pemetrexed 500 mg/m2 IV Q3W Arm A X 4 cycles Pemetrexed
Eligibility:
Stage IIIB/IV NSCLC
(malignant effusion)
ECOG PS 2
No prior chemotherapy
Stable CNS disease
Measurable disease
Adequate organ function
(including GFR≥ 45 ml/min)
Signed informed consent
Arm A
R A N D O M
I Z A T I O N
1:1
Stratification factors:
Stage: IIIB vs IV
Age: ≥70 vs <70
Wt loss: ≥5% vs <5%
X 4 cycles
Pemetrexed
500 mg/m2 IV Q3W +
Carboplatin
AUC 5 IV Q3W
n=137*
Arm B
Primary endpoint:
Overall Survival
Secondary endpoints:
Progression-free survival
Overall response ate
Safety
Pre-medications:
Vitamin B12: 1mg IM Injection
Folic Acid: 350-1,000mcg po daily
Dexamethasone 4mg po BID the day
before, the day of, and the day after
Median age: 65 in both groups
>70 years: 35.2% in pemetrexed group
36.8% in pemetrexed + carbo group 5 17

18. Overall Survival—PS2 trial
mOS 9.1 vs. 5.6m
HR=0.57 ( )
p=.001
Pem + Carbo
Pem alone
Lilenbaum, ASCO 2012, Abstr 7506

19. Overall Survival, elderly subset from PS2 trial
Lilenbaum, ASCO 2012, Abstr 7506

20. Carbo/paclitaxel vs. Carbo/Nab-paclitaxel
Albumin-bound paclitaxel
100 mg/m2 d1, 8, 15
Carboplatin AUC 6 d1
21 Day Cycles
No Premedication
Stage IIIb/IV NSCLC No prior therapy for metastatic disease
PS 0-1
N = 1,050
1:1
Paclitaxel 200 mg/m2 d1
Carboplatin AUC 6 d1
21 Day Cycles
With Premedication of
Dexamethasone + Antihistamines
Patients had no active brain metastases or ≥ grade 2 neuropathy at baseline
Socinski, et al ASCO LBA7511

21. Carbo/paclitaxel vs. Carbo/Nab-paclitaxel
Socinski, et al. JCO 30:17, 2012

22. Overall Survival Socinski et al, ASCO 2011, Abstr 7551 N/Events
Median OS
74/44
19.9 months
82/61
10.4 months
ab-P/C
P/C
* Subgroup analyses exploratory in nature
Socinski et al, ASCO 2011, Abstr 7551

23. Ongoing Second Line Phase II trial (LCCC1210)
Sites:
UNC
Cleveland Clinic
Upitt
Highlands Oncology
Rex Hospital
Fox Chase
Swedish Cancer Institute
Bon Secours
Inclusion:
At least 70 years of age
Prior non-taxane doublet
1 targeted agent allowed if mutation +
PS0-2
Adequate end-organ fxn (relatively liberal criteria)
NCT

24. Randomized Phase II First Line Trial
Carboplatin AUC 6 D1
Nab-paclitaxel 100mg/m2 D1, 8, 15
Randomization
Carboplatin AUC 6 D1
Nab-paclitaxel 100 mg/m2 D1, 8
Inclusion
1st line NSCLC
At least 70 years of age
NCT

25. CDDP/Pem vs. CDDP/Gem elderly data (Nonsquamous patients)
HR OS (all favor pem):
Subgroup <65: .89
Subgroup >65: .75
Subgroup <70: .83
Subgroup >70: .85
Gridelli et al, Clinical Lung Cancer, 13:5, 2012.

26. JMEN elderly data: Pem vs. placebo
HR OS (all favor pem):
Subgroup <65: .62
Subgroup >65: .87
Subgroup <70: .63
Subgroup >70: .81
Gridelli et al, Clinical Lung Cancer, 13:5, 2012.

27. Treatment Scheme of ECOG 4599D O M I Z E
Carboplatin (AUC 6)
Paclitaxel 200 mg/m2
Bevacizumab 15 mg/kg*
Non-squamous NSCLC
Absence of brain metastasis
ECOG PS 0 or 1
Informed consent
Carboplatin (AUC 6)
Paclitaxel 200 mg/m2
* Bevacizumab continued as monotherapy for CR/PR/SD after 6 cycles
Ramalingam, JCO 26:1, 2008

28. Efficacy of bevacizumab in Elderly in E4599 (carbo/paclitaxel +/- bev)
PFS OS
mPFS 4.5PC, 5.9m PCB, HR .76, p.063
mOS 12.1 PC, 11.3 PCB, HR .87
Ramalingam, JCO 26:1, 2008

29. BR.21 (erlotinib vs. placebo in 2nd line): overall survival
100 80 60 40 20
HR=0.70 (0.58–0.85) Stratified log-rank p<0.001
Percentage
Erlotinib
Placebo
Time (months)
At risk
Erlotinib Placebo
Shepherd F, et al. N Engl J Med 2005.

30. BR.21 elderly subset PFS Elderly OS Elderly
Toxicity: Greater for older patients compared to younger patients.
QOL: Favors erlotinib in elderly and to similar extent as younger patients.
Whearley-Price, JCO, 26:14, 2008

31. Pem vs doce elderly Hanna data: OS
<70 years
HR 1.02
Pem 7.8m
Doce 8m
>70 years
HR .86
Pem 9.5m
Doce 7.7m
Weiss et al, JCO 24:27, 2008.

32. The Less Functional Elderly
PS2
Renal dsyfunction
Hepatic dysfunction

33. Toxicity CP P G3/4 Toxicity (%) Anemia 3.9 11.7 Thrombocytopenia 1.0
1.0
Neutropenia
5.8
Febrile Neutropenia
2.9
1.9
Nausea/Emesis
Diarhea 2 1
Dyspnea
10.8
Grade 5 Events
3.9*
p=0.066
p=0.119
p=0.683
p=0.121
* Renal failure; Sepsis; Pneumonia, and Thrombocytopenia
Lilenbaum, ASCO 2012, Abstr 7506 33

34. Specific Drugs in Elderly Lung CA
Excretion
My opinion on geri friendliness
Cisplatin
Mostly urine
AWFUL
Carboplatin
GOOD; much better than cisplatin
Paclitaxel
Mostly feces
Moderate; better when given weekly
Docetaxel
AWFUL; dose reduce from 75mg/m2 to 60mg/m2 when needed
Nab-paclitaxel
VERY GOOD
Gemcitabine
Mostly renal
Good
Pemetrexed
Weiss, Expert Rev. Anticancer Ther. 12:1, 2012.

35. 6 FEB FEB 2002

36. 2009 Perspective
Mok, NJEM 2009

37. Probability of Survival Without Progression (%)
Crizotinib vs Standard Chemotherapy in ALK+ NSCLC (PROFILE 1007): PFS in 2nd or 3rd Line
100
Crizotinib
(n = 173)
Chemotherapy
(n = 174)
Events, n (%)
100 (58)
127 (73)
Median, mos
7.7
3.0
HR (95% CI)
0.49 ( )
P value
< .0001 80 60
Probability of Survival Without Progression (%) 40
ALK, anaplastic lymphoma kinase; HR, hazard ratio; NSCLC, non-small-cell lung cancer; PFS, progression-free survival. 20
Mos
Pts at Risk, n Crizotinib Chemotherapy
93 49
38 15
11 4
2 1
0 0
Shaw AT, et al. N Engl J Med. 2013;368:

38. PROFILE 1014: Crizotinib vs Pemetrexed/ Platinum in Advanced Untreated NSCLC
Adv ALK-pos nonsquamous NSCLC not previously treated (N = 343)
Crizotinib 250 mg BID
Primary endpoint: PFS
Pemetrexed + Cisplatin or
Carboplatin q3w x 6 cycles
100 80 60 40 20
Crizotinib
(n = 171)
Chemotherapy
(n = 169)
HR (95% CI)
P Value
ORR, % 74 45
< .001
mPFS, mos
10.9
7.0
0.45 ( )
ALK, anaplastic lymphoma kinase; BID, twice daily; NSCLC, non-small-cell lung cancer; ORR, overall response rate; q3w, every 3 weeks; PFS, progression-free survival.
PFS (%) 5 10 15 20 25 30 35
Solomon BJ, et al. N Engl J Med. 2014;371: Mok T, et al. ASCO Abstract 8002.

39. Nivolumab in SqCC Lung
Brahmer, NEJM 2015

40. Nivolumab in non-SqCC NSCLC
Paz-Ares ASCO 2015

41. Toxicity of PD1 Brahmer, NEJM 2015
Any way you cut it, pts feel better on Nivo:
Double the fatigue, 8 times the g3/4 fatigue
Dramatically less count supression; no F&N compared to 10% with doce
Brahmer, NEJM 2015

42. What we’re actually doing in the US: SEER/Medicare Database
Doublet, no platinum 6%
1.0
Chemotherapy Supportive care
HR 0.558
P<0.001
0.8
0.6
Single agents 23%
Survival
0.4
First Line
Platinum, other 19%
0.2
No chemotherapy 75% (n = 15,786) 6 12 18 24 30 36 42 48 54 60
Mos Since Diagnosis
Chemotherapy 26% (n = 5499)
NSCLC, non-small cell lung cancer
Mos Since Diagnosis
1.0
Other 5%
Platinum-doublet therapy Single Agent
HR 0.734
Platinum, taxane 48%
0.8
Survival
0.6
0.4
0.2 6 12 18 24 30 36 42 48 54 60
Mos Since Diagnosis
Davidoff AJ, et al. J Clin Oncol. 2010;28:

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